Planned usage:

Progress:

Metods:

Testing:

Notes:

PKMζ

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).[3][4][5] This theory arose from the observation that PKMζ perfused post synaptically into neurons causes synaptic potentiation, and selective inhibitors of PKMζ, when bath applied one hour after tetanization, inhibit the late phase or maintenance of LTP. Thus PKMζ is both necessary and sufficient for maintaining LTP. Subsequent work showed that inhibiting PKMζ reversed LTP maintenance when applied up to 5 hours after LTP was induced in hippocampal slices, and after 22 hours in vivo. Inhibiting PKMζ in behaving animals erased spatial long-term memories in the hippocampus that were up to one month old, without affecting spatial short-term memories,[5] and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.[6] In the neocortex, thought to be the site of storage for most long-term memories, PKMζ inhibition erased associative memories for conditioned taste aversion in the insular cortex, up to 3 months after training.[7][8] The protein also seems to be involved, through the nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.[9]PKMζ is thus the first molecule shown to be a component of the storage mechanism of long-term memory.

Recent research has demonstrated alteration in PKMζ in Alzheimer's disease (see Long-term potentiation), providing a potential link between this kinase and neurodegeneration.[10]

its pausible disrupted all sorts of memories by blocking PKMzeta, from old fears to motor skills to the location of objects.

note :how to make it specific without invasive techniqes ? reconsolidation window?

This time, a few days before their training, she infected the rats’ brains with viruses carrying PKMzeta. With extra copies of the protein at hand, the rats were more likely to remember their distaste for sweetener. Even if Shema injected the viruses a week after the rats’ training, when their aversion to the sweetener had started to fade, the extra PKMzeta enhanced their dulled memories.

note:

probably non specific

use in Alzheimer's disease?

problem with use viruses ?

more safe way of increasing PKMzeta ?

The viruses apparently weren’t just flooding the brain with PKMzeta, indiscriminately strengthening all the nearby synapses. Instead, the extra protein appears to have ended up in some synapses but not others. “This in a sense is just as remarkable,” says Sacktor. “You put in more of it and you don’t screw up the whole system. PKMzeta somehow knows how to fit into the memories that are already there.” Sacktor thinks that PKMzeta is drawn to itself. It somehow ends up in the right places and strengthens connections that have already been tagged by existing PKMzeta.

Even long-term memories are constantly on the verge of being erased. To keep them stable, we need to continually recreate a protein called PKMzeta. This molecule is the engine of memory, constantly whirring to store information in our brains. Give the engine a boost, and old memories gain a new lease on life. Switch it off, and we forget things…. permanently.

When we learn new things, PKMzeta shows up at the gaps between neurons (synapses) and boosts the signals that go across them. This strengthens the connections between the neurons on either side, and this network of bolstered connections is the physical embodiment of our memories. “

Scientists had found many molecules that were important for creating long-term memories, but not for storing them. Once memories were stable, you could knock out these molecules to little effect.

If you can erase or boost old memories by tweaking a single protein, then memories can’t be stored just by growing new synapses. Instead, Sacktor thinks that we store new memories by increasing the strength of synapses rather than their number, like towns that add extra lanes to the roads between them, rather than building new ones. “It’s a real revolutionary change in how neuroscientists have thought about memory,”

As memories are formed, synapses are busy places. The gene that provides instructions for making PKMzeta is always on, but in most neurons, there’s a blockade that prevents these instructions from being followed. It takes a large committee of signalling molecules to lift the blockade, start the production of PKMzeta, and ignite the memory engine.

Once it’s made, PKMzeta probably only lasts for a matter of days. So our synapses need to constantly replenish their supply of this protein, if we’re to keep stable long-term memories. Fortunately, a series of looping chemical reactions ensures that once neurons continue producing PKMzeta, they don’t stop. Once the memory engine starts whirring, it can carry on indefinitely. If the experiments with rats are a guide to what’s happening in people, “PKMzeta is staying in the same synapse probably for decades,” says Sacktor. “It’s not the same molecule but the population is being maintained at a high level for maybe a hundred years.”

PKMzeta works by increasing the levels of AMPAR, a protein that sits at synapses and allows fast signals to travel across them. Normally, AMPAR is caught in a tug-of-war between proteins that try to drag it towards the synapse and others that drag it away. PKMzeta swings the battle in favour of the former group. When it’s around, AMPAR moves towards the synapse in great numbers. Each arrival strengthens the synapse.

This is a constant battle. Other proteins are always trying to drive AMPAR away from the synapse, so PKMzeta has to fight to keep it there. This is why it’s so easy to erase memories with ZIP. If you get rid of PKMzeta, the tide of battle turns, AMPAR is driven away, the synapse weakens, and memories are forgotten.

It’s also universal to different types of memory. By using ZIP, Sacktor and others have managed to erase all sorts of long-term memories, from fears to locations to physical skills. “It applies to all parts of the brain that store different types of memory like the hippocampus that stores place information, or the amydgala that stores fear memories, or motor memories in the motor strip,” says Sacktor. “They’re all using PKMzeta.”

note: this may be problem to figured out noninvasive specific targeting

When we remember something, our memories once again enter a fragile state when they can be edited or overwritten – is this because PKMzeta must be destroyed and created afresh? How does newly formed PKMzeta manage to find synapses that are already tagged with this protein? What stops all the neurons in our brain from becoming saturated with PKMzeta? How does sleep affect the levels of PKMzeta at synapses? And does the memory engine start having problems as we grow older?

by injecting an inhibitor of PKMzeta called ZIP into the brains of lab rats. That erased the memories that were stored in that part of the brain, even for learning that had happened months before and even for really strong memories.

consolidation of memory – the transition from short to long-term memory. That’s not just one molecule, it’s hundreds, with many parts of the brain working in concert. There’s a transition period for an hour or two after you learn something when it’s not consolidated and when it’s easy to prevent it from doing so. Adding the modern view from our research onto this, we’d say that it’s easy to prevent the synthesis of PKMzeta, but once you make it, the memories become consolidated at specific synapses.

It’s likely that the reconsolidation is blocking the resynthesis of PKMzeta.

Reconsolidation window

Until you save the file, there’s a chance that you could lose the information. This vulnerable window can last for a couple of days. Only after that point does the memory become strong and long-lasting. This is called ‘consolidation’.

It’s not a permanent state. Whenever we remember something, the fragile window reopens. Again, it’s more like opening a computer document than getting notes out of a drawer. You could easily add, edit or delete information at a flick of a key. Every time we bring back an old memory, we run the risk of changing it. Again, it takes a while for this window of opportunity to close, for the reactivated memory to strengthen once more. This is called ‘reconsolidation’.

Propanolol

propranolol, commonly used to treat high blood pressure and prevent migraines in children

40 milligrams of propranol about 90 minutes before they were tested again. The others were given a placebo, but both groups reacted in the same way. Both of them could remember the fearful nature of the spider visuals, showing that the drug didn’t affect their ability to recall their old memory.

Two days later, and things were very different. Now, Kindt found that the while the volunteers on the placebo still feared the spiders, those who had been given propranolol no longer did. In fact, they were as difficult to startle as volunteers who had been conditioned in the first place. The drug had completely eliminated their fear response.

Propranolol does nothing on its own – it can’t exile fearful responses unless they are brought to the surface again. But once they are, the drug’s effects are quick and dramatic – just one reactivation under the influence of propranolol completely eliminated the response. However the volunteers still expected a shock when they saw the spidery images. They remembered that the pain of electricity would normally follow the sight of a spider – they just had no emotional reaction to that knowledge.

effect is amygdala specific

CREB

Han’s found that a protein called CREB is a molecular beacon that singles out neurons involved in remembering fearful experiences. When a rat experiences something scary, the CREB-neurons in a part of its brain called the amygdala are responsible for storing that memory – for producing what neuroscientists call its “trace”. When Han killed the amygdala’s CREB-neurons, he triggered selective amnesia in the rats, abolishing the specific fears they had been trained to feel. The memory loss was permanent.

Previously, Han showed that neurons in the amygdala are recruited to form part of a new memory trace depending on how much CREB they have. He bolstered the amount of this vital protein in a small group of neurons and found that, compared to their normal neighbours, these CREB-enhanced cells were three times more likely to be activated when he trained rats to fear a musical tone. Neurons that lacked CREB altogether were 12 times less likely to be activated when rats learned to be scared.